C A S E IX

1. BNP and the Hospitalized Patient Clive Rosendorff, M.D, Ph.D.,D.Sc.Med., F.R.C.P.Mount Sinai School of Medicine, New York, NY and theV.A. Medical Center, Bronx, NYMarch, 2005

2. C A S E IX William Brown, aged 76. In the laft stage of dropfy of the belly and legs, found a confiderable increafe of his urine by a decoction of Foxglove, but it was not permanent. William Withering, M.D. “An Account of the Foxglove and Some of its Medical Ufes, with Practical Remarks on Dropsy and Other Diseases” London, M,DCC,LXXXV, Page 128.

3. BNP Levels in the Hospitalized Patient • Number of admissions for HF in the US = 1 million per year. Annual cost = $56 billion. • Hospitalization accounts for 70-75% of direct cost of patient care. • Readmission after hospitalization for heart failure = 44% within 6 months. • For CVD = 6 million. Annual cost = $351 billion • In the US, about 1 million people die of CVD each year, about 40% of all deaths. • By 2020 CVD will cause 25 million deaths per year, worldwide.

4. BNP in the Hospitalized Patient • Diagnosis: HF vs. other causes of dyspnea. Systolic vs. Diastolic. • Prognosis: • Guide to therapy:

5. Diagnosis – HF vs. Other Causes of Dyspnea

6. BNP Levels in a Reference Population 1521 individuals: 983 disease free and 538 with either renal insufficiency, COPD, diabetes, or hypertension Wu, et.al. Clin Chem 2004; 50(5) 867-73

7. BNP Levels May be Elevated • Women • Elderly • Exercise • Renal Failure • Myocardial infarction • Cirrhosis • Open heart surgery • Sepsis • ?Mitral Regurgitation • ?Thyroid disease • ?Atrial fibrillation

8. BNP and the Severity of Heart Failure Wu, et.al. Clin Chem 2004; 50(5) 867-73

9. BNP IN SYSTOLIC HF. 821 Breathing Not Properly Multinational Study – 447 patients with acute dyspnea in the ED Maisel et al. JACC. 2003;41:2010-2017 34

10. Do High BNP Values Always Mean High LV Filling Pressure? Not always: • RV failure in cor pulmonale, pulmonary embolism or primary pulmonary hypertension. • Acute or chronic renal failure

11. Maisel, Rev Cardiovasc Med. 2002;3(suppl 4):S10-S17

12. Diagnosis – Systolic vs. Diastolic Failure

13. BNP in Patients with Systolic or Diastolic Dysfunction Breathing Not Properly Multinational Study – 447 patients with acute dyspnea Maisel et al. JACC 2003;41(11):2010-2017

14. CHF Diagnosis and Ventricular Dysfunction 2042 Randomly selected inhabitants of Olmstead County, MN. Ventricular dysfunction is greatly underdiagnosed in the community. Redfield et al. JAMA. 2003;289:194-202

15. Mortality for Persons with Normal and Impaired Diastolic Function. 1779 Inhabitants of Olmstead County, MN. Redfield et al. JAMA. 2003;289:194-202

16. BNP IN SYSTOLIC OR DIASTOLIC DYSFUNCTION 821 413 Breathing Not Properly Multinational Study – 447 patients with acute dyspnea in the ED Maisel et al. JACC. 2003;41:2010-2017 34

17. Prognosis

18. 1156 Hospitalized pts. With systolic HF (mean LVEF 21%), Rx with iv diuretics and vasodilators). Fonarow. Rev Cardiovasc Med. 2002;3(suppl 4):S18-S27

20. BNP and Pulmonary Wedge Pressure Kazanegra et al., J Cardiac Fail., 2001;7:21-29 Mean change per hour

21. BNP as an Aid to Prognosis 325 patients followed for 6 months after visit to ED for dyspnea. Harrison et al. Ann Emerg Med. 2002;39:131-138

22. BNP Quartiles in Patient Survival Probability of survival based on baseline BNP on 4300 patients taking an angiotensin receptor blocker (valsartan) in the Val-HeFT trial (LV EF<40% and LVIDd/BSA<2.9 cm/m2). Anand, et.al. Circulation.2003;107:1278-83

23. Predictors of In-Hospital Mortalityand Risk Stratification – Classification and Regression Tree (CART) Hospital for ADHF BUN > 43mg/dl BUN < 43mg/dl M = 2.7% M = 8.98% SBP< 115 mm Hg SBP> 115mmHg SBP< 115mmHg SBP> 115mmHg 2.1% 5.5% 6.4% 15.3% Cr > 2.75 Cr <2.75mg/dl Acute Decompensated Heart Failure National Registry (ADHERE) – 37,772 hospitalizations. BNP missing in 81.9% of records. Fanarow et al JAMA 2005;293:572-580 12.4% 21.9%

24. Cumulative Incidence of Death and Heart Failure According to the Plasma BNP Level at Base Line Framingham – 3346 persons without heart failure Highest third BNP; Male>12.8 pg/ml, Female>15.8 pg/ml Wang, T. J. et al. N Engl J Med 2004;350:655-663

25. ENTIRE-TIMI 23 - a multi-national trial that enrolled patients from 43 centers (tPA vs. tPA + abciximab vs. heparin/enoxaparin). • BNP measured in baseline samples from 438 patients presenting within 6 hours of STEMI. • Patients were followed for clinical outcomes, including death,recurrent myocardial infarction, and congestive heart failure through 30 days after enrollment.

26. BNP at Presentation and Prognosis in Post-MI Patients:An ENTIRE-TIMI 23 Sub-study BNP risk assessment performance was superior to troponin I or hs-CRP Mega et al. JACC 2004;44:335-339

27. Kaplan-Meier Curves Showing the Cumulative Incidence of Death at 10 Months, According to the Quartile of B-Type Natriuretic Peptide Level at Enrolment TIMI-16 (Orofiban vs Placebo) – 10,288 patients. Q1=5-44; Q2=44-81; Q3=81-138; Q4=138-1456 de Lemos, J. A. et al. N Engl J Med 2001;345:1014-1021

28. Association between the B-Type Natriuretic Peptide Level and the Mortality Rate at 10 Months, According to the Index Diagnosis TIMI-16 (Orofiban vs Placebo) – 10,288 patients de Lemos, J. A. et al. N Engl J Med 2001;345:1014-1021

29. Stepwise Logistic-Regression Model Showing the Association between Selected Base-Line Clinical Variables and the Odds Ratio for Death at 10 Months TIMI-16 (Orofiban vs Placebo) – 10,288 patients de Lemos, J. A. et al. N Engl J Med 2001;345:1014-1021

30. BNP as a Guide to Therapy

31. Fonarow. Rev Cardiovasc Med. 2002;3(suppl 4):S18-S27

32. Proposed algorithm for using BNP testing in the diagnosis of patients presenting with acute dyspnea. BHP Consensus Panel. CHF. 2004; 10[5 suppl 3]:1–30)2004

33. Four Hemodynamic Profiles

34. Use of ED BNP in Evaluation and Management of Acute Dyspnea. Mueller et al. N Engl J Med. 2004;350:647-654

35. How Often should BNP be Measured in the Hospital? BNP has a plasma half life of 20 minutes. Strategies: 1. Admission, discharge, or any major change. 2. 12-24 hours after any change in treatment. 3. If very sick patient in ICU without hemodynamic monitoring, then every 4-6 hours.

36. Causes of a BNP that does not Fall During Hospitalization • May be the patients “dry” BNP level. Usually NYHA IV with poor prognosis. • Another superimposed condition, e.g. pulmonary embolus. • Azotemia may down-regulate BNP clearance receptors • Diuresis may mobilize third space fluid, rather than lowering wedge pressure

37. BNP Results to Evaluate And Treat Heart Failure (BREATH) • Study Design • 1222 patients, hospitalized, EF<35%, BNP>400 pg/mL • Randomized to Control and BNP Guided • Outpatient follow-up period up to 12 months • Event driven study – 25% event rate in Control group • Primary End-Points: All cause mortality, rehospitalization or ER i.v. therapy for worsening heart failure.

38. Summary • HF is a major and increasing public health problem. • BNP has greatest diagnostic value if <100 pg/ml or >400 pg/ml. • Diastolic HF is common, has a considerable mortality and is underdiagnosed; BNP can help. • BNP changes with PCWP and is predictive of morbidity and mortality in both HF and MI. • Baseline BNP in the ED improves management and outcome. • No evidence yet that BNP guidance during hospitalization improves outcome.

40. END